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Plasmonics brings the molecular world into sharper focus

This story was originally published by Knowable Magazine.

In the battle against breast cancer, the drug Herceptin is a
steady ally, keeping some kinds of tumors at bay and helping people
live longer. Yet nearly all cancers eventually develop
resistance.

Until recently, the underlying cause of this resistance eluded
researchers. But then chemist Wei Wang developed a technique to
track how individual Herceptin molecules attach to cancer cells. He
found that a protein in the membranes of the resistant cells was
deforming the receptor molecules that Herceptin grabs onto, giving
the drug no handhold.

This medical insight owes a debt to physics — specifically, the
ability of metals to steer light on nanometer scales, a field of
research known as plasmonics. By introducing cancer cells to
Herceptin on one side of a gold wafer and watching changes in how
light bounced off the other side, the researchers could see how the
two parties — cancer cell and cancer drug — interacted, thus
revealing a crucial mechanism of Herceptin resistance.

People have been using metals to manipulate the passage of light
for centuries, though only recently has the phenomenon been used to
understand diseases like cancer. Large sheets of shiny metal —
a.k.a. “mirrors” — are like Do Not Enter signs for photons,
reflecting back these light particles in mostly unchanged states.
But microscopic metal flakes are different: They act more like
traffic cops, allowing certain colors of light to pass through and
blocking others.

One of the oldest examples of this phenomenon in action is a
fourth century Roman chalice known as the Lycurgus Cup. Normally,
the glass cup appears green and opaque. But if you illuminate the
goblet from within, the glass glows a translucent red. That’s
because nanometer-sized particles of gold and silver suspended in
the glass reflect green light and allow red light to pass.

In creating the cup, Roman craftsmen had stumbled upon a synergy
between electrons, metals and light that no one would understand
for another 16 centuries: The electrons in some metals will
resonate when tickled with just the right wavelength of light,
which alters the path of the light itself.

Today, the field of plasmonics is flourishing. In the last 20
years or so, researchers have taken a much more deliberate approach
to exploiting this behavior, creating tailored nanostructures that
compress and manipulate light into volumes roughly the size of
single molecules.

The ability to focus light on the nanoscale turns out to have
scores of potential applications, says Caltech plasmonics pioneer
Harry Atwater. The many uses are helping to solve problems in
chemical sensing, data transfer, cancer therapy and navigation for
self-driving cars. “That’s why this field is so exciting and why
it’s been so compelling … it’s so interdisciplinary,” Atwater
says.

Graphic shows potential and current applications now being explored for plasmonics, including in invisibility cloaks, superfast optical computers, higher-resolution imaging devices, better color sensitivity in cameras, new solar cells, faster fiber optic connections, tumor-killing cancer therapies and lasers for self-driving cars.

The ability to manipulate light and electrons with nanometer
precision turns out to be useful in a wide range of applications
such as super hi-res imaging, targeted therapies for tumors,
guidance for self-driving cars, and perhaps for even more fanciful
goals, such as making everyday objects invisible.

Shedding light on biomolecules

One of the most successful applications of plasmonics is
biosensing, wherein researchers try to detect the presence (or
absence) of biologically relevant molecules. Normally, these are
much too small to see with light, and though there are ways to tag
them, these techniques are often expensive or cumbersome or alter
the molecules in ways that hinder their study. Plasmonics offers an
alternative by confining light to molecule-sized volumes. Under
such circumstances, “what you can achieve is very strong
interaction of light with matter,” says Hatice Altug, a researcher
at the Federal Institute of Technology in Lausanne, Switzerland.
And that makes the light very sensitive to changes in, or the
presence of, individual molecules within those volumes. (For a more
thorough review of how plasmonics helps with biosensing, see this
2018 paper in Chemical Reviews.)

Wang, of China’s Nanjing University, and colleagues wanted to
bring this power to the field of drug development. Part of the
process of designing new drugs is understanding how the molecules
interact with cells in the body, but that typically requires
monitoring the interaction one cell at a time, which is very labor
intensive. If there were ways to see many drug molecules
interacting with many cells simultaneously, Wang says, that could
really speed things along.

One tried-and-true technique for tracking such interactions is
electrochemistry — running an electrical current through a
collection of molecules and cells. By tracking changes in the
current, researchers can measure the rate at which molecules attach
to and detach from the cells.

A row of six images of a cell under a microscope over a period of about 40 seconds. The center of the cell changes color as an opening in the cell membrane develops and then closes.

Pulses of electricity increase a cell membrane’s conductivity
(red areas), which creates an opening in the barrier that allows
delivery of molecules like drugs or DNA. Visualizing the process is
possible thanks to a plasmonics-based electrochemical imager, which
reveals when the membrane opens.

CREDIT: W. WANG ET AL / NATURE CHEMISTRY
2011

But electrochemistry doesn’t allow researchers to pinpoint these
interactions with any spatial precision. A researcher might measure
electrical current flowing through some cells and know that it’s
hindered by molecules attaching, but be blind to exactly where. In
the case of Herceptin resistance, that would mean knowing that
there’s been an overall change in how frequently Herceptin is
sticking to cells and then breaking off, but not knowing where the
change is happening.

Guided by the light

To get the precision they needed, Wang and colleagues created a
plasmonics-based electrochemical imager. As he and others describe
in the 2017 Annual Review of Analytical Chemistry,
instead of just applying a voltage to some cells and tracking how
the ensuing electrical current changes as molecules arrive and
depart, they also measured how light was reflected and absorbed by
a gold wafer to see just where the current got held up, and by how
much.

It’s the same principle as the Lycurgus Cup. In this case,
however, the light is aimed at one gold wafer, 50 nanometers thick.
On one side of the wafer is a small box filled with an electrolyte
solution in which scientists can place molecules and cells. A red
light illuminates the other side, and a camera measures how much of
this red light bounces off the wafer.

The researchers apply an oscillating voltage to the whole setup,
and this sends current coursing through the solution, drawing
electrons into and out of the gold. The shifting density of
electrons in the gold changes how much light gets reflected to the
camera. At some densities, the light bounces off, while at others
the light energy triggers waves of electrons in the gold known as
plasmons that skim its surface, much like ripples moving across a
pond. As the voltage goes up and down, electrons scurry in and out
of the gold, and the amount of reflected light pulses in sync.

Cell-molecule interactions are detectable because the setup is
affected by the behavior of those molecules and cells in the fluid
on the other side of the plate. Cells sitting close to the backside
of the gold will hold back some of the current — casting an
electrical “shadow” on the gold plate, pinpointing the cell’s
location. Now if a molecule attaches to the cell’s membrane, the
cell’s electrical properties will change, which will slightly
brighten or dim its electrical shadow. This changes how light
reflects off the metal at that spot, and the camera records the
changes.

Graphic illustrates the details of the plasmonic effect. The drawing shows an experimental plasmonics set-up made up of a thin metal plate with molecules attached to its underside. Some molecules in the solution below are binding to some of the molecules on the plate. Above the plate, a laser shines light at an angle onto the metal plate, generating a “plasmon wave,” light then bounces off the plate at specific angles into a camera.

Light normally bounces off a thin metal film. But at just the
right angle, the light triggers a plasmon wave — ripples of the
metal’s electrons — and little light gets reflected. The exact
angle depends partly on what molecules are present on the other
side of the metal film. When molecules in solution, such as a
cancer drug, attach to other molecules on the metal film, this
pairing up alters the reflected light, which researchers can
monitor for insight into how the molecules are interacting.

Wang’s team used such an approach to figure out how Herceptin
behaved differently around tumor cells that had developed
resistance to the drug. They took resistant and nonresistant tumor
cells and stuck them on the gold film. Then they added Herceptin to
the electrolyte solution. Normally, Herceptin attaches to a protein
in the cell membrane and thereby inhibits growth. This binding
alters the plasmon wave of electrons and thus the light reflected
off the metal.

But the researchers found that the reflections looked different
near places on the gold that had been layered with drug-resistant
tumor cells. Some of the proteins in those cells let go of the
Herceptin dozens of times faster than normally, which altered the
electrical current through those cells. This, in turn, changed
whether plasmons formed in the gold and modified the pattern of
light reflection.

With a view to drug development, Wang says that he has now begun
studies of neuron and heart cells, in particular the protein
channels used to shuttle sodium and potassium ions in and out of
the cells. These ion channels are “the windows of communication
between the cell and its environment,” he says. “If you’re
developing a new drug, you need to evaluate the potential side
effects to the heart.”

It is slow, laborious work, Wang adds, but a plasmonics-based
electrochemical imager could speed things up.

Plasmonics is also being applied to other kinds of imaging,
delivering resolutions that traditional microscopes cannot achieve
and acting as a highly sensitive biosensor for a range of
applications. Researchers hope that these tabletop devices can be
shrunk into handheld ones; Altug, for one, envisions a future with
portable, low-cost, easy-to-use plasmonics-based drug detectors and
other biosensors that don’t require trained researchers. They might
even be attached to cellphones.

“You could use it in the field to monitor water, security in an
airport or in resource-limited settings such as a third-world
country,” she says. “We’re not quite there yet, but there is a big
push.”

This story was originally published by Knowable Magazine. Knowable Magazine is an independent journalistic endeavor from Annual Reviews.

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